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Molecular and Cellular Biology, January 2002, p. 148-160, Vol. 22, No. 1
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.1.148-160.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

SRm160 Splicing Coactivator Promotes Transcript 3'-End Cleavage

Susan McCracken, Mark Lambermon, and Benjamin J. Blencowe*

Banting and Best Department of Medical Research, C. H. Best Institute, University of Toronto, Toronto, Ontario, Canada M5G 1L6

Received 27 July 2001/ Returned for modification 10 September 2001/ Accepted 4 October 2001

Individual steps in the processing of pre-mRNA, including 5'-end cap formation, splicing, and 3'-end processing (cleavage and polyadenylation) are highly integrated and can influence one another. In addition, prior splicing can influence downstream steps in gene expression, including export of mRNA from the nucleus. However, the factors and mechanisms coordinating these steps in the maturation of pre-mRNA transcripts are not well understood. In the present study we demonstrate that SRm160 (for serine/arginine repeat-related nuclear matrix protein of 160 kDa), a coactivator of constitutive and exon enhancer-dependent splicing, participates in 3'-end formation. Increased levels of SRm160 promoted the 3'-end cleavage of transcripts both in vivo and in vitro. Remarkably, at high levels in vivo SRm160 activated the 3'-end cleavage and cytoplasmic accumulation of unspliced pre-mRNAs, thereby uncoupling the requirement for splicing to promote the 3'-end formation and nuclear release of these transcripts. Consistent with a role in 3'-end formation coupled to splicing, SRm160 was found to associate specifically with the cleavage polyadenylation specificity factor and to stimulate the 3'-end cleavage of splicing-active pre-mRNAs more efficiently than that of splicing-inactive pre-mRNAs in vitro. The results provide evidence for a role for SRm160 in mRNA 3'-end formation and suggest that the level of this splicing coactivator is important for the proper coordination of pre-mRNA processing events.

* Corresponding author. Mailing address: Banting and Best Department of Medical Research, C. H. Best Institute, University of Toronto, 112 College St., Room 410, Toronto, Ontario, Canada M5G 1L6. Phone: 416-978-3016. Fax: 416-978-8528. E-mail: b.blencowe{at}utoronto.ca.

Molecular and Cellular Biology, January 2002, p. 148-160, Vol. 22, No. 1
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.1.148-160.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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